South Africa and Zimbabwe are experiencing explosive HIV epidemics while New York is among the few places in the USA where the HIV epidemic continues to grow. A unique trans-Atlantic consortium from these three settings, which draws on existing collaborations and pools the expertise and experience available in 3 HIVNET sites and 2 AACTG sites, is being proposed as the Southern Africa - New York HIV vaccine trials unit (SANY-HVTU). The SANY-HVTU creates a trans- disciplinary team with research leadership in HIV/AIDS prevention and therapy, combined with expertise in immunology, virology, vaccinology, epidemiology, biostatistics, ethics, behavioral science, clinical trial management and community mobilization. Ongoing research within the proposed research team includes characterizing circulating viral strains, defining disease pathogenesis, investigating HIV resistant sex workers for correlates of protection, describing background HLA distributions, investigating immune responses in acute seroconversion and devising new assays (e.g. CTL by intracellular cytokine staining) thereby providing essential information for HIV vaccine development. Researchers in the SANY-HVTU, working with both subtypes C and B, have been involved in community-based HIV vaccine preparedness studies, development of HIV vaccines (VEE, DNA and oligomeric glycoprotein vaccines) and HIV vaccine clinical trials (Alvac, AIDSVax and gp160 vaccines). In addition, researchers in the SANY-HVTU have extensive experience in therapeutic AIDS trials, non-HIV vaccine trials and HIV prevention trials with one-year follow-up rates averaging between 85% and 95%. The SANY-HVTU proposes a range of cohorts including South African truck stop sex workers (incidence rate: 18.2% per year), youth in Hlabisa, South Africa (incidence rate: 14.8% per year), New York intravenous drug users (incidence rate: 4.5% per year), Zimbabwean factory workers (incidence rate: 3% per year), South African Sugar Mill workers (incidence rate: 2.5% per year), New York gay men (incidence rate: 1-2.2% per year), and New York women at heterosexual risk (incidence rate: 0.7-1.7% per year). While the phase I and phase II capability is well developed in the SANY-HVTU, the greatest strength of the proposed unit is its capability to conduct phase III trials in large very high risk cohorts. The logistics of efficient recruitment and follow-up are well planned, and, in some instances, draw on the latest in global positioning systems technology to assist in locating subjects. Community preparations for HIV vaccine trials are at an advanced stage; Community Advisory Boards have been established and Community Education plans are being implemented already. In year one, the SANY-HVTU proposes to enroll 80 subjects (40 in each of two phase I HIV vaccine trials) in South Africa, and 60 subjects (30 in a phase I and 30 in a phase II trial) in New York, while undertaking preparatory activities for HIV vaccine trial enrollment in year two in Zimbabwe.